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Fatal Rat-Bite Fever --- Florida and Washington, 2003

Rat-bite fever (RBF) is a rare, systemic illness caused by infection with
Streptobacillus moniliformis. RBF has a
case-fatality rate of 7%--10% among untreated patients
(1). S. moniliformis is commonly found in the nasal and oropharyngeal flora
of rats. Human infection can result from a bite or scratch from an infected or colonized rat, handling of an infected rat,
or ingestion of food or water contaminated with infected rat excreta
(1). An abrupt onset of fever, myalgias, arthralgias,
vomiting, and headache typically occurs within 2--10 days of exposure and is usually followed by a maculopapular rash on
the extremities (1). This report summarizes the clinical course and exposure history of two rapidly fatal cases of RBF identified
by the CDC Unexplained Deaths and Critical Illnesses (UNEX) Project in 2003. These cases
underscore the importance of 1) including RBF in the differential diagnoses of acutely ill patients with reported rat exposures and 2) preventing zoonotic infections among persons with occupational or recreational exposure to rats.

The patient was admitted to the intensive care unit, where she became increasingly hypoxic with marked
anemia (hemoglobin: 8.6 g/dL [normal: 12--16 g/dL]) and increasingly
severe thrombocytopenia (32,000
platelets/µL). She was treated with ciprofloxacin, metronidazole, and vancomycin for possible gram-negative sepsis and received two blood transfusions; however, she died approximately 12 hours after
admission. A maculopapular rash was noted postmortem.
No autopsy was performed.

Peripheral blood smears obtained before death revealed abundant neutrophils and intracellular collections of
filamentous bacteria (Figure). Premortem blood from a tube containing no additives or separators was inoculated onto a blood agar
plate and incubated in CO2 at
95ºF (35ºC). After
72 hours, the culture demonstrated slight growth of gram-negative
filamentous bacteria. UNEX was contacted for assistance, and diagnostic specimens were submitted to CDC for further
laboratory evaluation. At CDC, the isolate was subcultured onto media enriched with 20% solution of sterile normal rabbit serum and
incubated in a candle jar for 48 hours. Biochemical analyses identified the bacterial isolate as
S. moniliformis. The 16S rRNA gene sequences amplified from DNA extracted from the patient's blood and the bacterial isolate were consistent with S.
moniliformis.

The patient had been employed at a pet store. She was bitten on her right index finger by a rat in the store 2 days
before symptom onset and 4 days before arriving at the ED. She self-treated the wound by using antiseptic
ointment immediately after being bitten. In addition, she had regular contact with several pet rats, cats, a dog, and an iguana at her home; however, no bites from these animals were reported. None of the animals were tested for
S. moniliformis.

Washington. In late November 2003, a previously healthy woman aged 19 years was pronounced dead on arrival at
a hospital ED. No laboratory studies were performed in the ED. An acquaintance reported that the patient had experienced a
3-day history of fever, headache, myalgias, nausea, and profound weakness without cough, vomiting, diarrhea, or rash.
Before her transport to the ED, she exhibited anxiety, confusion, and labored breathing. ED staff noted that she appeared
jaundiced. The body was transported to the coroner's office, where an autopsy was performed.

Cultures of blood and tissue from autopsy were negative for pathogenic organisms. A toxicology screen was
negative. Serologic assays for leptospirosis, Epstein-Barr virus, cytomegalovirus, and viral hepatitis were negative for recent
infection. Histopathology revealed findings suggestive of a systemic infectious process that included disseminated
intravascular coagulopathy and inflammatory cell infiltrates in the liver, heart, and lungs. UNEX was contacted for assistance, and project staff facilitated the submission of diagnostic specimens to CDC for further laboratory evaluation.
Immunohistochemical assays performed at CDC for
Leptospira spp., Bartonella quintana, spotted fever and typhus group rickettsiae,
flaviviruses, hantaviruses, and influenza viruses were negative. Clusters of filamentous bacteria were identified in sections of the liver and kidney by using a silver stain. The 16S rRNA gene sequence amplified from DNA extracted from
paraffin-embedded, formalin-fixed samples of liver and kidney was consistent with
S. moniliformis.

The patient worked as a dog groomer and lived in an apartment with nine pet rats. One pet rat with respiratory
symptoms had recently been prescribed oral doxycycline after having been evaluated at a veterinary clinic. Doxycycline was
subsequently used to treat a second ill rat. None of the rats were tested for
S. moniliformis. The patient had no known animal bites
during the 2 weeks preceding her death.

Editorial Note:

Although rapidly fatal pediatric cases of RBF have been described previously
(2,3), similar mortality among adults has not been reported. Mortality attributed to severe systemic complications (e.g., endocarditis, myocarditis, meningitis, pneumonia, or multiple organ failure) has been documented in certain adult patients
(1,4). Both patients described in this report died within 12 hours of presentation, allowing little opportunity for assessment and treatment. These case reports demonstrate that infection with S.
moniliformis can cause fulminant sepsis and death in previously healthy adults. As a
result, prevention of severe disease might depend on
increasing the awareness of appropriate risk-reduction activities and
possible symptoms of RBF among persons who have exposure to rats. Intravenous penicillin is the treatment of choice, and
prompt therapy can prevent severe complications
(1). Because rapid laboratory confirmation of infection with
S. moniliformis might not be possible, clinicians should consider initiating empiric therapy for patients with a compatible clinical presentation
and exposure history.

Clinicians should consider RBF in the differential diagnosis for unexplained febrile illness or sepsis in patients reporting
rat exposure. Initial symptoms might be nonspecific (Box), but a maculopapular rash and septic arthritis
commonly develop (1,5). However, as demonstrated by the cases in this report, patients can have severe disease before the onset of
typical symptoms. Despite its name, approximately 30% of patients with RBF do not report having been bitten or scratched by a
rat (1,5). Risk factors for RBF include handling rats at home and in the workplace (e.g., laboratories or pet stores). RBF is rare
in the United States, with only a few cases documented each year
(1,6,7). However, because RBF is not a nationally
notifiable disease, its actual incidence has not been well described.

In the cases described here, diagnosis of RBF was delayed in part because of the inability to rapidly isolate or
identify S. moniliformis. If infection with
S. moniliformis is suspected, specific media and incubation conditions should be used
(8) (Box). In the absence of a positive culture, identification of pleomorphic gram-negative bacilli in appropriate specimens might support a preliminary diagnosis (1). In the event of an unexplained death in a person with rat exposure, performing
an autopsy might also be critical to identifying an etiology.

Because of the high prevalence of colonization and asymptomatic infection with
S. moniliformis among rodents (Box), testing and treatment of rats is not practical. Disease prevention should center on risk reduction among persons with frequent rat exposure. Adherence to simple precautions while handling rats can reduce the risk for RBF and other potential
rodent-borne zoonotic infections, wound infections, and
injuries. Persons should wear gloves, practice regular hand washing,
and avoid hand-to-mouth contact when handling rats or cleaning rat cages
(1,9). If bitten by a rat, persons should promptly
clean and disinfect the wound, seek medical attention, and report their exposure history. A tetanus toxoid booster should
be administered if >10 years have lapsed since the last dose
(9,10).

Clinicians should contact their state health departments for assistance with diagnosis of unexplained deaths or
critical illnesses and cases or clusters of suspected RBF or other zoonotic infections. UNEX coordinates surveillance for unexplained deaths possibly attributed to infection
throughout the United States. Cases are reported by a network of health
departments, medical examiners/coroners, pathologists, and clinicians. Epidemiologic and clinical data are collected, and available clinical and pathologic specimens are obtained for reference and diagnostic testing at state, CDC, and other laboratories. State and local health departments may contact UNEX for assistance with the evaluation of unexplained deaths that occur in
their jurisdictions.

National Association of State Public Health Veterinarians. Compendium of measures to prevent disease and injury associated with
animals in public settings. St. Paul, MN: National Association of State Public Health Veterinarians; 2004. Available at
http://s94745432.onlinehome.us/AnimalsInPublic2004.pdf.

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